Role of Uric Acid in Cardiovascular and Renal Disease We are currently having an epidemic of obesity, with two-thirds of the US population either overweight or frankly obese. Twenty-seven percent of our population have the metabolic syndrome, a known prediabetic condition, and 7% have diabetes. It is critical that we identify potential mechanisms to account for this great epidemic. While there are no doubt multiple causes, including excessive caloric intake and physical inactivity, we have identified another possible mechanism. Specifically, fructose, present in certain sweeteners and sugar, can rapidly induce metabolic syndrome in rats and has also been epidemiologically linked with the rise in obesity. Fructose is unlike all other sugars in that it raises uric acid rapidly in the blood. During the previous RO-1 we have found that uric acid has multiple effects on blood pressure, vascular disease, kidney disease and inflammation, and in particular we have found that uric acid can reduce nitric oxide release from vascular cells. We have further shown that fructose, by way of increasing uric acid, can cause obesity, insulin resistance and lipid abnormalities in rats, and that this can be partially prevented by lowering uric acid. In this application we will further investigate the mechanism by which uric acid contributes to this syndrome, and also dissect how fructose activates this pathway that leads to obesity and the metabolic syndrome. Studies will include determining the critical features about fructose that are necessary to induce the syndrome, with an emphasis on the type of fructose and its role in hypertension. We will also investigate how the rise in uric acid secondary to fructose causes features of the syndrome, with an emphasis on how fructose and uric acid disturb the normal vasculature, converting it from a noninflamed and dilated system to one that is inflamed and constricted. Finally, we will explore the possibility that fructose and uric acid may have direct effects on fat cells. Understanding the pathways by which uric acid, and fructose, can cause metabolic syndrome may give new insights into the pathogenesis of the obesity epidemic, with its impact on cardiovascular and kidney disease. Project Narrative: This study looks at the role of uric acid and fructose in the development of metabolic syndrome. The role of these factors in this syndrome, have not been widely studied. Identifying a casual role for these factors could lead to new treatments for metabolic syndrome.